Review
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For numbered affiliations see
end of article.
Correspondence to
Professor Christophe Baudouin,
Quinze-Vingts National
Ophthalmology Hospital,
28 rue de Charenton,
Paris 75012, France;
cbaudouin@15-20.fr
Received 30 June 2015
Revised 29 October 2015
Accepted 28 November 2015
Published Online First
18 January 2016
Open Access
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To cite: Baudouin C,
Messmer EM, Aragona P,
et al. Br J Ophthalmol
2016;100:300–306.
300
Revisiting the vicious circle of dry eye disease:
a focus on the pathophysiology of meibomian
gland dysfunction
Christophe Baudouin,1,2 Elisabeth M Messmer,3 Pasquale Aragona,4 Gerd Geerling,5
Yonca A Akova,6 José Benítez-del-Castillo,7 Kostas G Boboridis,8
Jesús Merayo-Lloves,9 Maurizio Rolando,10 Marc Labetoulle11
ABSTRACT
Meibomian gland dysfunction (MGD) is the most
frequent cause of dry eye disease (DED). Eyelid
inflammation, microbial growth, associated skin disorders
as well as potentially severe corneal complications
culminate to make MGD a complex multifactorial
disorder. It is probable that MGD is a heterogeneous
condition arising from any combination of the following
five separate pathophysiological mechanisms: eyelid
inflammation, conjunctival inflammation, corneal
damage, microbiological changes and DED resulting
from tear film instability. The pathogenesis of both MGD
and DED can be described in terms of a ‘vicious circle’:
the underlying pathophysiological mechanisms of DED
and MGD interact, resulting in a double vicious circle.
The MGD vicious circle is self-stimulated by
microbiological changes, which results in increased
melting temperature of meibum and subsequent
meibomian gland blockage, reinforcing the vicious circle
of MGD. Meibomian gland blockage, dropout and
inflammation directly link the two vicious circles. MGD-
associated tear film instability provides an entry point
into the vicious circle of DED and leads to
hyperosmolarity and inflammation, which are both a
cause and consequence of DED. Here we propose a new
pathophysiological scheme for MGD in order to better
identify the pathological mechanisms involved and to
allow more efficient targeting of therapeutics. Through
better understanding of this scheme, MGD may gain
true disease status rather than being viewed as a mere
dysfunction.
INTRODUCTION
The meibomian glands, found in the upper and
lower eyelids, excrete lipids onto the ocular surface
that forms the outermost layer of the tear film,
lubricating the ocular surface during blinking and
protecting against tear evaporation.1 2 Through
dysfunction of the meibomian glands, reduced lipid
secretion may contribute to tear film instability and
entry into the vicious circle of dry eye disease
(DED).3–6 Indeed, meibomian gland dysfunction
(MGD) is the most common cause of evaporative
DED7 8 and is found even in situations previously
considered to be primary ( pure) aqueous-
deficient DED.9 Moreover, MGD is correlated
with ocular discomfort during activities requiring
relevant visual tasks, such as the use of video
display terminals.10 Although the precise aeti-
ology and pathophysiology of MGD remain to be
Baudouin C, et al. Br J Ophthalmol 2016;100:300–306. doi:10.1136/bjophthalmol-2015-307415
determined, in 2011 the International Workshop
on MGD proposed the following definition for
MGD: “a chronic, diffuse abnormality of the mei-
bomian glands, commonly characterised by ter-
minal duct obstruction and/or qualitative/
quantitative changes in the glandular secretion. It
may result in alteration of the tear film, symptoms
of eye irritation, clinically apparent inflammation,
and ocular surface disease”.11 The International
Workshop on MGD successfully marshalled a
large literature base into an exhaustive scheme of
the mechanisms underlying the pathogenesis of
MGD and the numerous interacting pathways
involved.1 However, the complexity of this
scheme may limit its relevance in clinical practice.
Here we introduce a new pathological scheme of
MGD, which may be easier to interpret in clinical
practice, to facilitate the understanding of the
mechanisms that underlie its development and
relationship with DED and to allow more effi-
cient treatment of both MGD and DED.
PREVALENCE OF MGD
Within the general population, precise estimates
of MGD prevalence are elusive as rates vary geo-
graphically and, until recently, a clear definition
of MGD was lacking. The prevalence of MGD
varies considerably in published studies.12–16
Generally, it is higher in Asian populations,
ranging from 46% to 70%, whereas in Caucasian
populations the MGD prevalence ranges from
3.5% to 20%.11 It should be noted that the
higher prevalence of MGD in Asian populations
is partly due to inconsistent diagnostic criteria
among countries.17 For example, the Beijing
study included both the clinical signs and the
symptoms of MGD in their definition whereas
other studies did not.7 Moreover, certain diag-
nostic criteria may be unable to distinguish
between MGD and aqueous deficient DED,
which may also point towards a strong relation-
ship between the two diseases.18 The
International Workshop on MGD suggests estab-
lishing a set of MGD-specific symptoms to aid in
diagnosis.7 The prevalence of MGD is also
affected by age, with older patients at increased
risk of developing MGD. In a group of patients
aged <30 years and ≥60 years, 33% and 72%
had MGD, respectively.19 Prevalence rates also
increase if the mixed forms of DED, which
include MGD and aqueous tear deficiency, are
considered.20

CLASSIFICATION AND AETIOLOGY OF MGD
According to the report of the Definition and Classification
Subcommittee of the International Workshop on MGD,
MGD may be classified as a low- or high-delivery state,
according to the extent of meibomian lipid secretion.21 The
low-delivery state, which is the most common form of MGD,
is associated with deficiencies in meibomian secretion, and it
may be further characterised as obstructive, with cicatricial
and non-cicatricial subcategories, or hyposecretory.21
Hyposecretory MGD is associated with gland atrophy.
Obstructive MGD is the most prevalent form of low-delivery
state MGD and is caused by hyperkeratinisation, which is
influenced by sex, hormonal disturbances, topical medications
and age.21 Interestingly, emerging evidence from both animal
and human studies suggests that age-related cell signalling
changes within the meibomian gland can lead to gland
atrophy,22 23 suggesting that some cases of age-related
MGD could be classified as hyposecretory rather than
obstructive MGD.
Increased meibum viscosity, which is present in all cases of
obstructive MGD, may arise because of changes in meibum
composition.21 High-delivery state MGD, also known as hyper-
secretory MGD, is characterised by the release of large amounts
of meibum at the lid margin in response to pressure on the
eyelids. Hypersecretory MGD has been associated with sebor-
rhoeic dermatitis in 100% of cases, but it may also be associated
with rosacea.8 21 In both hyposecretory and hypersecretory
MGD, the lipids produced are modified (non-canonical), chan-
ging the composition and reducing the quality of the tear film,
thus leading to symptoms of eye irritation, inflammation and
DED.11 Although exhaustive, the complexity of the aetiological
classification and associated pathological scheme proposed by
the International Workshop on MGD may be difficult to inter-
pret in clinical practice as both rare (eg, genetic atrophy of mei-
bomian glands) and more common mechanisms (eg, rosacea) are
included at the same level.
Multiple causes may be responsible for the development of
MGD-associated tear film alterations, including eye surgery or
systemic hormonal treatments such as oestrogen replacement
therapy in women and anti-androgen therapy in men.1 The
latter suggests that hormonal changes contribute to the aetiology
of MGD.8 Moreover, ophthalmic factors such as aniridia, prolif-
eration of Demodex folliculorum, eyelid tattooing, floppy eyelid
syndrome, giant papillary conjunctivitis and trachoma are also
believed to correlate with MGD.8
IDENTIFYING THE PATHOPHYSIOLOGICAL MECHANISMS
OF MGD
MGD is associated with multiple pathological mechanisms
including inflammation, microbial factors and lipid deficiencies.1
Eyelid inflammation, microbiological proliferation, release of
toxic cytokines onto the cornea and hyper-evaporation combine
to create a picture of a benign dysfunction. However, this is
often painful and dangerous to the cornea when inflammatory
infiltrates, phlyctens, keratitis or peripheral ulcers complicate
the meibomitis.8 With such variable and complex mechanisms
involved in MGD, analysing the pathology and even defining
the disease is challenging. Is MGD a disease of the eyelids, tear
film, cornea or the entire ocular surface? Moreover, are the
associated microbial, metabolic, inflammatory or endocrine dis-
eases related to the eye or the skin? The International
Workshop on MGD chose to focus on DED as a consequence
of MGD but did not consider meibomitis or eyelid or corneal
Baudouin C, et al. Br J Ophthalmol 2016;100:300–306. doi:10.1136/bjophthalmol-2015-307415
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changes; therefore, the pathophysiology of MGD was not fully
resolved.24
In our scheme, the stasis of the meibum, which may be
caused by obstruction, dropout or inflammation of the meibo-
mian gland, can promote the growth of bacteria. This may then
increase the release of esterases and lipases by commensal bac-
teria of the eyelids. As a consequence of this increased enzyme
activity, bacteria can change the viscosity of the meibum, leading
to further stasis of the meibum within the meibomian glands,
and generate free fatty acids, which in turn causes inflammation
and hyperkeratinisation.1 5 These changes in lipid composition
may determine the occurrence of foam in the tear film, often
visible on the lid margin of patients with MGD.25 26
Although a critical analysis of the literature on age-related
MGD is beyond the scope of this review, age has been asso-
ciated with specific pathogenic effects on meibomian gland
structure, such as altered localisation of the peroxisome
proliferator-activated receptor gamma, a lipid-activated
hormone receptor that regulates lipid synthesis and cell differen-
tiation,23 27 or meibomian gland atrophy through a loss of
MGD progenitors.22 Additionally, accumulation of reactive
oxygen species with age may play a role in the pathogenesis of
MGD.28 These mechanisms may underlie atrophic non-
obstructive MGD in the older population.29 Although the
pathophysiology of age-related MGD may be distinct from
non-age-related MGD, subsequent meibomian gland dropout29
may allow entry into the vicious circle of MGD.
It is likely that MGD is a heterogeneous complex condition
arising from any combination of the following five separate
pathophysiological mechanisms: eyelid inflammation, conjunc-
tival inflammation, corneal damage, microbiological changes
and tear film instability-associated DED. The International
Workshop on MGD proposed a complex pathway involved in
the self-enforcing vicious circles of MGD (figure 1).21 Although
these proposed pathways are probably correct, they may be too
focused on DED as a final consequence of MGD to be of real
practical application. We therefore present the previously pub-
lished vicious circle of DED,3 illustrating its various entry
points, and then we build on this to develop the double vicious
circle that demonstrates the interacting pathophysiologies of
MGD and DED.
VICIOUS CIRCLE OF DED
In 2007 and 2013 we proposed new patterns for understanding
DED (figure 2).3 6 Tear film instability, tear hyperosmolarity,
apoptosis and inflammation contribute to the pathophysiology
of DED. These aetiologies are not mutually exclusive, but rather
connected to one another in a cyclical manner, acting as entry
points into the vicious circle of DED. As such, DED may be
described as an autonomous self-sustaining disease state that is
progressively disconnected from its initial causes. In the vicious
circle, rapid break-up of the tear film after blinking (tear film
instability) leads to local drying and hyperosmolarity of the epi-
thelial surface. In turn, this leads to apoptosis, inflammation and
a loss of mucin-producing goblet cells. This cascade of mechan-
isms, involving osmotic, mechanical and inflammatory stress,
destroys goblet cells and defence systems of the ocular surface
leading to further damage of the tear film, and thus closes the
circle. A major cause such as Sjögren’s syndrome can stimulate
all states of the vicious circle. Other factors such as corneal
surgery, low humidity and high airflow, contact lens wear, aller-
gies or preservatives may disrupt reflex tear delivery to the
ocular surface or increase tear film instability, thus initiating
entry into the vicious circle.5
301
 Review
Figure 1 Pathways involved in the pathophysiology of meibomian gland dysfunction (MGD) proposed by the 2011 International Workshop on
Meibomian Gland Dysfunction.3 60
The vicious circle scheme allows us to understand why, once
the cycle is initiated, the continuous environmental challenge
acting on a compromised ocular surface allows the vicious circle
to perpetuate, even if the initial cause has been removed or
reduced (figure 2).3 The vicious circle scheme may also promote
the development of therapeutic strategies that can simultan-
eously target the multiple mechanisms underlying the patho-
physiology of DED.30 For example, tear substitutes with
osmoprotective properties3 31–33 may act on multiple points to
break the vicious circle of DED.3 33 34 Topical anti-
inflammatory strategies, such as those containing steroids or
cyclosporine, target inflammation and help halt the cycle.35 36
Thus, a better understanding of the vicious circle may improve
DED management with existing therapies and could also aid in
the development of new therapies. We identified MGD as a
potential entry point into the vicious circle of DED and, from
this, the complexity of the relationship between DED and MGD
became apparent.3 In order to further elucidate the interacting
pathophysiological mechanisms of DED and MGD, we turn to
the vicious circle in more detail, this time focusing on MGD.
DED AND MGD: THE DOUBLE VICIOUS CIRCLE
A new DED scheme that encompassed MGD and illustrated
how the related pathophysiological mechanisms underlying
DED and MGD combine to form one chronic form of
MGD-associated DED needed to be drawn, and this took the
form of a double vicious circle illustration (figure 3).
Meibomian gland changes act as an entry point into both DED
and MGD loops of the double vicious circle; however, as illu-
strated by the circle, there is no set starting point and MGD can
302 Baudouin C, et al. Br J Ophthalmol 2016;100:300–306. doi:10.1136/bjophthalmol-2015-307415
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originate elsewhere. Our clinical observations reveal that
patients with Sjögren’s syndrome can develop MGD through
chronic inflammation-induced keratinisation and subsequent
dropout and atrophy of the meibomian glands. Although inflam-
mation initiates entry, it is the meibomian gland changes that
connect the two vicious circles of MGD and DED. The follow-
ing four sequential events comprise the MGD loop: stasis of the
meibum, bacterial proliferation, release of lipases and esterases,
and increased meibum melting temperature. This illustrates how
dropout, blockage and/or inflammation of the meibomian
glands lead to stasis of the meibum inside the gland, and prolif-
eration of bacteria and mites including Staphylococcus spp and
Demodex folliculorum. D. folliculorum is known to promote
bacterial proliferation and cause inflammation of the eyelid and
possibly the conjunctiva.37 38 This ingrowth of bacteria
enhances the production of lipid-degrading lipases and esterases
that increase the viscosity and melting temperature of the
meibum, reducing its secretion onto the surface of the tear film
and thus closing the self-sustaining MGD circle.1 Furthermore,
upper and lower eyelid laxity may exacerbate reduced meibum
drainage through decreased muscle pressure on the meibomian
glands.35 39
Skin diseases (eg, ocular rosacea) are also believed to play a
role in MGD pathology; approximately 90% of patients with
ocular rosacea show eyelid changes that are similar to those
observed in patients with MGD.40 The absence of normal
meibum reduces the lipid content of the tear film, allowing
entry into the DED loop of the vicious circle, in which the lipid-
deficient tear film promotes increased tear evaporation, hyperos-
molarity and inflammation.41 The missing link between

Figure 2 Proposed vicious circle of
the pathology of dry eye disease.
MGD, meibomian gland dysfunction.
inflammation of the eyelid and lacrimal effects was identified
based on the observation that exposure of ocular surface epithe-
lia to desiccating stress led to the release of cornified envelope
precursors by the ocular epithelium.42 This was accompanied by
keratinisation of meibomian gland orifices, which caused further
meibomian gland blockade and atrophy as well as loss of mucin-
filled goblet cells and entrapment of mucin within the remaining
goblet cells, blocking delivery of mucin to the ocular surface
and contributing to the development of DED.42 Keratinisation
of meibomian glands is believed to arise from hyperosmolarity
and inflammatory cytokine-induced expression of corneal enve-
lope precursors.43 44 Other pathogenic mechanisms associated
with DED include increased age and the use of benzalkonium
chloride-containing glaucoma medications.13 45 46 Meibomian
gland blockage, dropout and inflammation directly link the
DED and MGD vicious circles.
Although MGD is the most common cause of evaporative
DED,7 8 Bron et al41 proposed an additional hypothesis where
MGD-associated DED leads to a compensatory increase in tear
production, followed by compromised lacrimal function and
reduced tear secretion that leads to a mixed form of DED com-
prised of both evaporative and aqueous subtypes.41 Support for
this hypothesis has been recently published; fluorescein score,
tear film break-up time and Schirmer test scores were signifi-
cantly worse in patients with aqueous-deficient DED compared
with MGD, suggesting that increased tear production may com-
pensate, at least for a while, for meibomian gland loss in
Baudouin C, et al. Br J Ophthalmol 2016;100:300–306. doi:10.1136/bjophthalmol-2015-307415
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patients with early-stage MGD.47 This hypothesis illustrates
how all ocular surface components are inter-related.
Imaging techniques such as in vivo confocal microscopy
(IVCM), optical coherence tomography and keratography allow
visualisation of the cellular and anatomical structures of the
cornea and ocular surface.48–50 These techniques can therefore
provide valuable information on the relationship between DED
and MGD.51 Infrared imaging revealed an increased meibomian
gland dropout score in patients with Sjögren’s syndrome com-
pared with control subjects without DED,49 suggesting that
patients with Sjögren’s syndrome may be at a greater risk of
developing MGD. Moreover, IVCM revealed that the meibo-
mian glands of patients with Sjögren’s syndrome had higher
acinar density, smaller diameters, a greater density of perigland-
ular inflammatory cells and higher secretion reflectivity com-
pared with patients with MGD.51 These observations support
an essential role of MGD in DED and could provide a histo-
pathological basis for the previously mentioned mixed form of
aqueous and evaporative DED. Additionally, in a retrospective
observational pilot study of patients with MGD-associated
refractory DED, IVCM revealed clinically non-apparent inflam-
mation of the palpebral conjunctiva despite improvements in
tear film break-up time, an increased number of meibomian
glands yielding secretion and a normal clinical examination
post-treatment, suggesting that IVCM may also be a useful tool
for identifying the underlying causes of symptom-sign disparity
in patients with MGD.52 Further studies are needed to truly
303
 Review

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Figure 3 Importance of meibomian gland dysfunction in the vicious circle of the pathology of dry eye disease.61

understand how imaging can advance our understanding of the
relationship between MGD and DED.
WHAT IS THE PURPOSE OF THIS NEW DOUBLE VICIOUS
CIRCLE?
Beyond its educational and scientific interest, the double vicious
circle may be used for understanding and revealing the
complexity of the pathophysiological mechanisms underlying
DED and MGD, as well as a tool to focus and guide therapy.
Figure 4 illustrates how different therapies, some acting at mul-
tiple points of the circle, may be used to disrupt the vicious
circles of MGD and DED. Eyelid hygiene, consisting of eyelid
warming and massage, reduces the proliferation of bacteria that
are believed to increase the melting temperature of meibum, in

Figure 4 Different therapies may target particular pathophysiological mechanisms that underlie the vicious circle of dry eye disease.
304 Baudouin C, et al. Br J Ophthalmol 2016;100:300–306. doi:10.1136/bjophthalmol-2015-307415

addition to melting the altered meibomian lipids to improve
their secretion.35 53 Eyelid hygiene devices such as the MGDRx
Eyebag (The Eyebag Company, West Yorkshire, UK),
Blephasteam (Laboratoires Théa, Clermont-Ferrand, France)
and LipiFlow (TearScience, North Carolina, USA) have been
shown to improve symptoms in patients with MGD.54–57 The
anti-inflammatory and antimicrobial effects of oral tetracycline
derivatives such as doxycycline, and antibiotics, including azi-
thromycin, may reduce bacterial proliferation and prevent
inflammation-induced keratinisation of meibomian glands to
improve meibum secretion.35 58 59 Moreover, figure 4 illustrates
how therapies that have the potential to break one of the
vicious circles, such as tear substitutes, may impact on the other
via indirect effects on meibomian gland blockage, dropout and
inflammation.
It seems apparent that a diagnosis of MGD is based on a set
of signs and symptoms and that its true nosology remains to be
determined. The double vicious circle scheme defined here
creates the foundation for the classification of MGD; it high-
lights the pathophysiological mechanisms involved and
addresses the basics of treatment. Taken together, this new
scheme perhaps gives MGD true disease status and identifies it
as more than a simple dysfunction.
Author affiliations
1
Quinze-Vingts National Ophthalmology Hospital, University Versailles St Quentin en
Yvelines, Versailles, France
2
UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
3
Department of Ophthalmology, Ludwig Maximilian University, Munich, Germany
4
Institute of Ophthalmology, University of Messina, Messina, Italy
5
Department of Ophthalmology, University Hospital Düsseldorf, Heinrich-Heine
University, Düsseldorf, Germany
6
Department of Ophthalmology, Bayindir Hospital, Ankara, Turkey
7
San Carlos University Hospital, Complutense University, Madrid, Spain
8
Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki,
Greece
9
University of Oviedo and Fernández-Vega Ophthalmological Institute, Oviedo, Spain
10
Department of Neuroscience, Ophthalmology, and Genetics, University of Genoa,
Genoa, Italy
11
Ophthalmology Department, Bicêtre University Hospital, Le Kremlin-Bicêtre, France
Twitter Follow Kostas Boboridis at @KBoboridis
Acknowledgements The authors thank Newton Healthcare Communications for
writing and editorial support, which was funded by Allergan, UK.
Contributors CB defined the concept and scope of the review. EMM, PA, GG,
YAA, JBdC, KGB, JM-L, MR and ML provided critical review of the manuscript. All of
the authors were involved in the finalisation of the manuscript.
Funding Allergan provided funding for the meetings and for the development of
this manuscript. The authors were involved with the entire process, from design to
critical revision of the manuscript, and maintained complete control over the
direction and content of the paper.
Competing interests CB has received research grants and consulting fees from
Alcon, Allergan, Santen and Théa. EMM has acted as an advisor and presenter for
Allergan, Alcon, Bausch & Lomb, Croma-Pharma, MSD, Oculus, Santen, Théa and
Ursapharm. PA has acted as a consultant and presenter for Allergan, Alcon Italy,
Bausch & Lomb, Santen, Medivis, Théa, Eupharmed and Farmigea and has received
a research grant from SOOFT Italia. GG has acted as a consultant or speaker for
Allergan, Alcon, Bausch & Lomb, Chiesi, Oculus, Santen, Théa, TearLab and
TearScience. YAA has acted as an advisor and presenter for Allergan, Théa, Bausch
& Lomb, and Alcon. JBdC has acted as a consultant for Allergan, Bausch & Lomb,
Théa, Alcon and Santen. KGB declares financial relationships with Allergan, Alcon
and Théa. MR declares financial relationships with Allergan, Bausch & Lomb,
Farmigea, Théa, Alcon, Eupharma, Santen/Novagali and AlfaIntes. JM-L has received
research grants from Théa and has acted as a consultant for Allergan. ML has acted
as a consultant for Allergan, Alcon, Bausch & Lomb, Farmigea, MSD, Santen/
Novagali and Théa.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
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permits others to distribute, remix, adapt, build upon this work non-commercially,
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licenses/by-nc/4.0/
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